The Children'sOncology Group (COG) is a new multidisciplinaryclinicaltrialsgroup resultingfrom the unificationof the four pediatriccooperativegroups. It is thelargestchildhoodcancer research organization in the worldand encompasses approximately238 pediatriccancer programs as clinicaltrial sites throughoutall of NorthAmerica, Australia, and several institutionsin Europe. It is exclusivelywell poisedto translate basic biologystudies intoclinicalinvestigationsand to develop translationalapproaches through human proofof principle,toxicity assessment, identificationof efficacy, and ultimately,incorporationintoestablished treatmentsto improve outcome and/or decrease toxicity.COG representsthe legacyof four groups,the oldest of which existedfor nearly 50 years. Currently, 48,259 patients accruedto clinicaltrialsare in active follow-up;over 2,500,000 person years of life have been saved. Although childhoodcancer mortality has decreased by 50% in the lasttwo decades and by 25% inthe past decade, nearly 2,500 childrenand adolescents die from cancer annuallyinthe U.S. alone. The majorityof these deaths can be attributedto specificpediatric cancersfor which new therapeuticapproachesmust be devised. Improvementin the cure ratesfor these high-riskcancers is more likelyto emerge as a result of the identificationof biologicfeatures whichpredict resistanceand, more importantly, by the identificationof new anti-cancer agents with novel mechanisms of action,whose efficacy might be predictedon the basis of specificunique molecular abnormalitiesdetected in cancer cells. COG is also uniquelyable to establishfor the first time a North America-wide population-basedregistry of childhoodcancerto investigate,utilizingcase control studies, potentialepidemiologicassociations,includinggenetic alterationsand ultimatelyinteractions of genes with the environment.COG, through a series of hypothesis-drivenresearch studies,seeks to maximize cure rates for children with cancer; to achieve an expanded understandingof tumor and hostbiology;to elucidatenew therapeutic strategies and to build on the concept of risk-adjustedtherapy; and to reduce treatment-related toxicityand morbidity, thereby optimize quality of life and survival.The proposed research is aimed at reducingdeaths from childhood cancer by 20% and increasing 5-year disease-free survival (cure) rates to >85% duringthe studyperiod.